Optically active aliphatic alcohols are common substructures in natural products and are also useful chiral building blocks for the synthesis of chiral drugs. However, although in recent decades considerable attention has been devoted to the development of efficient methods for the synthesis of optically active aliphatic alcohols, including highly efficient asymmetric hydrogenation of aryl alkyl ketones to prepare optically active chiral alcohols, it still remains an open challenge for most of the methods are limited to synthesize the category of aryl alkyl type of optically active chiral alcohols. It still lacks of efficient method to prepare optically active aliphatic alcohols (de Vries, J. G.; Elsevier, C. J. The Handbook of Homogeneous Hydrogenation; Wiley-VCH: Weinheim, 2007; Zhao, B.; Han. Z.; Ding, K. Angew. Chem., Int. Ed. 2013, 52, 4744; Xie, J.-H.; Zhou, Q.-L. Acta Chris. Sinica 2012, 70, 1427). Catalytic asymmetric catalytic hydrogenation of aliphatic carbonyl compounds is an effective and atom economic, way to obtain chiral aliphatic alcohols, but this method is limited to the preparation of sterically hindered chiral aliphatic alcohols substituted with alkyl groups. For example, Noyori et al use chiral ruthenium diphosphine/amine pyridine catalysts in the catalytic hydrogenation of tert-butyl substituted di-alkyl alcohols with the enantioselectivity 98% ee (Ohkuma, T.; Sandoval, C. A.; Srinivasan, R; Lin, Q.; Vei, V Mufiiz, K. Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288). While low enantioselectivity can be obtained in the catalytic hydrogenation of aliphatic ketones with little difference of the alkyl groups existed by the two sides of carbonyl groups.
Besides asymmetric catalytic hydrogenation method, using enzyme or chiral catalysts to resolve racemic alcohols has been studied to be a method to obtain active chiral alcohols, still, these methods are mainly used to prepare active chiral alcohols with the two alkyl groups which lied by two sides of hydroxyl existed big difference (Vedejs, E.; Jure, M. Angew Chem. Int Ed. 2005, 44, 3974; Pellissier, H. Adv Synth. Catal. 2011, 353, 1613.). In addition, the kinetic resolution method under developed was existed the problem that transferring one enantiomer to ketone or ester.
For this reason, to overcome the defects existed in preparing optically active aliphatic alcohols, we develop a highly efficient kinetic resolution of racemic δ-hydroxy ester via asymmetric catalytic hydrogenation of ester group. And this method has been efficiently obtained chiral δ-hydroxy esters and δ-1,5-diols in good yields with high enantioselectivities. It is the chiral spiro pyridylamidophosphine ligand complexed with Iridium to form the catalysts (Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int Ed. 2011. 50, 7329; Zhou, Q.-L.; Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X. WO2012065571A1; Zhou, Q.-Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.: Wang, L.-X. CN102040625 B) developed by us that realized the highly efficient kinetic resolution of racemic δ-hydroxy ester via asymmetric catalytic hydrogenation of ester group. Optically active chiral δ-hydroxy esters are obtained with the yield of 43-49 percent and with the enantioselectivity of 90-99 percent ee. Optically active chiral δ-1,5-diols are obtained with the yield of 44-50 percent and with the enantioselectivity of 91-97 percent ee. The kinetic resolution of asymmetric catalytic hydrogenation of ester group has high efficiency, and can obtain good results even reducing the amount of catalyst to 0.001 mol %. So the present kinetic resolution of racemic δ-hydroxy ester via asymmetric catalytic hydrogenation has the advantages of high efficiency, high enantioselectivity, economic, good operation, environmental friendly and can be used to industry manufacturing. The present kinetic resolution method of optically active aliphatic alcohols has been successfully used in asymmetric synthesis of chiral drugs (R)-lisofylline and natural drugs (+)-civet, (−)-indolizidine 167B and (−)-coniine via asymmetric catalytic hydrogenation.